In this study, we employ in vitro models to study the factors that can induce mesenchymal-to-epithelial transition MET) or epithelial-to-mesenchymal transition (EMT) of pancreatic precursor cells and their mechanisms of action with a goal to develop a system that could be used for cell replacement therapy for patients with diabetes mellitus. Development of the endocrine pancreas includes a series of early events wherein precursor cells migrate as mesenchymal cells to form epithelial aggregates that subsequently differentiate into islets of Langerhans. We use primarily cells derived from human cadaveric pancreata, human islet-derived precursor cells (hIPCs), to study MET and EMT. We have established a novel cell culture system using hIPCs that allows for proliferation of these precursor cells for at least 30 generations. The proliferating mesenchymal cells can be induced to transition to epithelial cells that subsequently differentiate into insulin-expressing cells in vitro. In preliminary experiments, we found that epithelial cell clusters (ECCs) formed from hIPCs can transition back to cells exhibiting a mesenchymal phenotype. Although we originally hypothesized that hIPCs may be derived by in vitro EMT of mature beta cells, we have recently provided evidence that mouse IPCs are not derived from beta cells. Nevertheless, regulation of MET, an initial step in differentiation toward beta cells, and EMT of ECCs is an important site of control for the use of hIPCs for cell replacement therapy. We have found that platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) regulate hIPC EMT (and proliferation). We are pursuing studies to better understand these processes.